Melanoma accounts for 4% of all skin cancer diagnoses but contributes to 75% of deaths from skin cancer, where the incidence of melanoma and death rates from melanoma continue to rise, each year in the Western world.
In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat. Diagnosis of melanoma is commonly based on pathology and immunological staining and prognostication is mainly based on Breslow score (depth of invasion of the primary lesion).
MicroRNA (miR) molecules are major regulators of a large proportion of animal genes or the transcriptome. Association of various miRs with diseases or susceptibility to disease is known in the art. For example, U.S. Patent Application Publication No. 2007/0072204, discloses a method for diagnosing a subject with various cancers based on the expression level of mir17 (mir17-92 cistron).
Typical treatments of melanoma include surgery removal of the tumor, immunotherapy, chemotherapy and radiotherapy among others. The majority of all melanomas are caused by a missense mutation (V600E) in the B-Raf oncogene. Thus, various agents targeted to the inhibition of the V600E gene product have been developed and include, for example, the compound PLX4720 (known also as Vemurafenib), currently under human clinical studies. Additional novel approaches for melanoma therapy include agents which augment the anti-tumor immune response such as Ipilimumab, which blocks CTLA4 inhibition of lymphocyts, thereby enhancing the immune response directed to the tumor.
Creighton et al. (Cancer Res., Mar. 1, 2010; 70(5):1906-15) found miR-31 to be under-expressed in ovarian cancer cell lines, and showed that its forced expression induced p53-mediated apoptosis in different cell lines.
It has been shown by Liu et al. (Clin. Cancer Res., 15:1177-1183, 2009) and others that miR-133 is down-regulated in various cancer cell lines. Others have shown that miR133a is a tumor suppressor in bladder cancer (Chiyomaru et al., British Journal of Cancer 102(5):883-91, 2010) and in esophageal cell carcinoma (Kano et al., Int. J. Cancer, Mar. 2, 2010, Epub: http://www.ncbi.nlm.nih.gov/pubmed/20198616).
MiR-184 was also found to be associated with squamous cell carcinoma of tongue (Wong et al., Clin. Cancer Res., 14(9):2588-92, 2008).
Lee et al. (PLoS Comput. Biol., Apr. 1, 2010, 6(4):e1000730) indicates that miR-204 is an onco-suppressor in head and neck tumor metastasis.
U.S. Patent Application Publication No. 2006/0105360 discloses a method of diagnosing whether a subject has or is at risk of developing cancer, including melanoma, based on measuring the copy number of at least one miR gene, including, miR-301.
U.S. Patent Application Publication No. 2008/0026951, discloses the association of various miRs with different diseases, including the association of miR-17 with colon cancer; miR-31 with colon and thyroid cancers; miR-133a with cardiac hypertrophy and lupus; miR-184 with lupus and miR-204 with Alzheimer's disease.
U.S. Patent Application Publication No. 2008/0306006, discloses the association of various miRs, including, miR-31; miR-34a; miR-184prec; miR-185 and miR-204, with solid tumors, specifically, breast cancer; lung cancer, prostate cancer, stomach cancer, colon cancer and pancreatic cancer.
According to U.S. Patent Application Publication No. 2008/0076674 mi34a and miR185 are associated with breast cancer. Takahashi et al. (PLoS One, 4 (8):e6677, 2009) discloses that miR185 induces cell cycle arrest in lung cancer cell lines.
U.S. Patent Application Publication No. 2009/0263803 discloses that miR-29a and miR-29c, are differentially expressed in lymph nodes obtained from melanoma patients compared to healthy control subjects.
A method for diagnosing a cancer, including melanoma, in a subject, comprising determining an amount of one or more miRs including miR-324-3p, is disclosed in U.S. Patent Application Publication No. 2010/0196426, wherein if there is a measurable difference of said miR, the subject is diagnosed as having the cancer.
U.S. Pat. No. 7,897,356 discloses that miR-374, among other miRs, is a specific biomarker for melanoma. However, according to US 2011/0107440, the expression of miR-374, miR-29a, miR-29c, miR-324-3p and miR-451, among other miRs, is indicative of non-melanoma skin cancer.
Identification of miRNAs that regulate the aggressive phenotype of melanoma cells is disclosed by the inventors of the present invention in a paper entitled: “Regulation of cancer aggressive features in melanoma cells by microRNAs”, published after the priority date of the present application (Greenberg et al. PLoS One. 2011 Apr. 25; 6 (4):e18936).
There is an unmet need for effective method of diagnosing, staging, prognosticating and treating metastatic melanoma.